This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The main aim of this project is to compare the effects of in vivo blockade of Programmed Death-1 (PD-1) and its ligands, PD-L1 and PD-L2, in SIV-infected rhesus macaques. PD-1 is an immuno-inhibitory receptor of the Ig superfamily that has been implicated in T lymphocyte exhaustion observed in chronic virus infections, including HIV and SIV. We recently showed that in vivo blockade of PD-1 using an antibody to PD-1 in SIV-infected rhesus macaques is safe and results in improved T and B lymphocyte responses, and prolongs survival. While PD-1 is expressed mainly on activated hematopoietic cells, PD-L1 and PD-L2 show a much wider expression pattern, including expression in tissues and on non-hematopoietic cells. To better understand the role of the PD-1/PD-L pathway in impaired immune responses in SIV infection, we will administer antibodies to PD-L1 and PD-L2 in rhesus macaques at the early chronic stage of SIV infection. Thirty animals were infected with SIV and have been sampled at regular intervals for T cell function assays (intracellular cytokine assays, phenotyping) and B cell function assays (phenotyping, total and SIV-specific antibody responses), as well as viral load measurements for 12 weeks. After 18 weeks of infection, the animals will be divided into 4 groups, with each group receiving either control Ab, anti-PD-1 Ab, anti-PD-L1 Ab or anti-PD-L2 Ab, over the course of 2-3 months. The animals will thereafter be followed for 6 months to study the effects of treatment on viral load, and to thoroughly characterize their immune responses to the different treatments.